Synthesis and Biological Evaluation of Substituted Flavones as Gastroprotective Agents

Abstract

Flavone (1) was found to protect against ethanol-induced gastric damage in rats; however, it is known that certain compounds in the flavone class, including flavone itself, are inducers of hepatic drug metabolizing enzymes. With the hope of identifying gastroprotective flavones that have minimal effects on drug metabolizing enzymes, we have synthesized and evaluated selected flavone analogs. Gastroprotective potency in the ethanol model was retained by methoxy substitution in the 5-position (4) and by methoxy (12) or methyl (14) substitution in the 7-position. A number of substituted analogs of the potent molecule 5-methoxyflavone (4) were also synthesized, and in many cases, these substitutions provided gastroprotective molecules. In order to assess liver enzyme induction potential, two of the gastroprotective flavones, 7-methoxyflavone (12) and 5-methoxy-4'-fluoroflavone (26), were examined for their effect on liver microsomal cytochrome P450 and 7-ethoxyresorufin O-dealkylase (CYP1A) activity. These two compounds caused minimal changes in the cytochrome P450 concentration and were considerably less potent than beta-naphthoflavone as inducers of CYP1A enzyme activity. Furthermore, following oral administration to rats, 5-methoxy-4'-fluoroflavone (26) was found to protect against indomethacin-induced gastric damage. These results indicate that, through appropriate substitution, flavones can be obtained that are gastroprotective but have minimal effects on drug-metabolizing enzymes.

Empirically predicted 13C NMR chemical shifts for 8‐hydroxyflavone starting from 7,8,4′‐trihydroxyflavone and from 7,8‐dihydroxyflavone

“…Calculated 13 C chemical shifts (δ mhf8 , in ppm) for 8-hydroxyflavone. The 13 C chemical shifts reported by Ares et al [5] have been assigned on a matching basis Recently, Park et al [6] published the 1 H NMR and 13 C chemical shifts for flavone and 19 substituted flavones among which was 7,8,4 -trihydroxyflavone; the solvent was dimethylsulphoxide-d 6 . The predictive tool of Burns et al [4] can be operated in reverse to obtain the 13 C chemical shifts for 8-hydroxyflavone using the measured values of 13 C chemical shifts for 7,8,4 -trihydroxyflavone, 7-hydroxyflavone, and 4 -hydroxyflavone.…”

“…However, the general utility of this tool is impeded by the lack of the 13 C NMR spectrum of 8-hydroxyflavone, so the tool cannot be applied to predict 13 C NMR spectra of a flavonoid substituted with a hydroxyl group at the C8 position. Ares et al [5] have reported an exclusive account of the 1 H NMR and 13 C chemical shifts of 8-hydroxyflavone prepared by them by the conversion of 8-methoxyflavone into 8-hydroxyflavone 13C NMR chemical shifts for 8-hydroxyflavone Table 1. Calculated 13 C chemical shifts (δ mhf8 , in ppm) for 8-hydroxyflavone.…”

“…Also shown in Table 1 The unassigned 13 C chemical shifts for 8-hydroxyflavone reported by Ares et al [5] have been assigned by matching them with the average values of the two sets of calculated 13 C chemical shifts for 8-hydroxyflavone. In this case, the minimum average absolute difference between the data of Ares et al [5] and the predicted 13 C chemical shifts of 8-hydroxyflavone was 0.63 ppm.…”

An Effective Synthesis of 5,4'-Disubstituted Flavones via a Cesium Enolate Assisted Intramolecular ipso-Substitution Reaction

“…5. The prepared novel flavones (3c, 3e, 3f, 3g, 3l-n) and the other flavones, which have not been examined for AR antagonist activity (3a, 9) 3b, 16) 3d, 9) 3h, 17) 3i, 16) 3j, 18) 3k, 19) 10a, 20) 10b 20) ), will be tested in an in-vitro reporter gene assay in the near future.…”

Flavonoid-lnduced Gastroprotection in Rats: Role of Blood Flow and Leukocyte Adherence

“…also indicate that certain flavonoid derivatives (e.g., Meciadanol and Solon) exhibit gastroprotective properties [6][7][8][9][10].…”